AMITIZA (lubiprostone) 8 mcg Twice Daily in the Management of Irritable Bowel Syndrome with Constipation in Women 18 Years of Age and Older

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1 APRIL 2009 PRODUCT INFORMATION GUIDE DAVID MACK / PHOTO RESEARCHERS, INC. AMITIZA (lubiprostone) 8 mcg Twice Daily in the Management of Irritable Bowel Syndrome with Constipation in Women 18 Years of Age and Older SPECIAL ADVERTISING SECTION This product information guide is funded by Takeda Pharmaceuticals North America, Inc. AMITIZA is a registered trademark of Sucampo Pharmaceuticals, Inc. PHG0802

2 DAVID MACK / PHOTO RESEARCHERS, INC. AMITIZA (lubiprostone) 8 mcg Twice Daily in the Management of Irritable Bowel Syndrome with Constipation in Adult Women 18 Years of Age and Older AMITIZA 8 mcg twice daily was approved by the FDA in April 2008 for the treatment of Irritable Bowel Syndrome with Constipation in women 18 years old. DEFINITION Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder, generally defined as a group of symptoms resulting from changes in bowel function without intestinal structural or biochemical abnormalities. 1 Symptoms of IBS include abdominal discomfort, bloating, and altered bowel habits, which can include diarrhea, constipation, or alternating diarrhea and constipation. 1 IBS has been further classified into subtypes according to stool patterns. IBS with constipation, or IBS- C, is characterized by hard or lumpy stools 25% of the time or more, and loose or watery stools less than 25% of the time. 2 Other subtypes of IBS include IBS with diarrhea (IBS-D) and IBS with alternating diarrhea and constipation (IBS-A). The prevalence of IBS in North America is approximately 10%-15%; of these patients, about 20% suffer from IBS-C. 1,3 DIAGNOSIS The diagnosis of IBS-C is made after a complete medical history is obtained and physical examination is performed. IBS-C has no biochemical or structural abnormalities associated with it, so there are no specific tests that can confirm the diagnosis. However, it can be easily diagnosed in the 2

3 Management of IBS-C in Women 18 Years of Age and Older doctor s office without additional testing. 4 According to the American College of Gastroenterology, there is no need to perform routine sigmoidoscopy; colonoscopy; barium enema; stool tests for occult blood, ova and parasite or culture; or thyroid function tests in patients with IBS-C complaints who have no alarm symptoms. 1 Alarm symptoms include items such as blood in the stool, a greater than 10- pound weight loss, family history of colon cancer, recurring fever, anemia, or chronic severe diarrhea. Several symptom-based criteria have been used to diagnose IBS-C, including the Manning Criteria and the ROME Criteria. These criteria are most useful for standardizing enrollment of patients into clinical trials, and less useful for clinicians in their clinical practice decisions about diagnosis and treatment of IBS-C. 5 Identification of IBS-C can be made if abdominal pain or discomfort is present over at least 6 months and is active within the past 3 months, with 2 or more of the following: 1) relieved with defecation; 2) onset associated with a change in frequency of stool; and 3) onset associated with a change in form (appearance) of stool. Patients can be sub-typed as having IBS-C if they also experience 2 of 3 of the following: 1) <3 spontaneous bowel movements per week, 2) >25% hard stools, and 3) >25% spontaneous bowel movements associated with straining. 2 TREATMENT The goal of treatment is to improve symptoms of IBS-C such as abdominal discomfort, bloating, and constipation. The general approach to the treatment of IBS-C depends in large part on the type of symptoms the patient is experiencing and their severity. Some patients with mild symptoms may find a slow increase in dietary fiber, a healthy amount of exercise and restful sleep, and education about IBS-C are adequate to improve their condition. 5 Patients whose lives are significantly affected by symptoms typically require both lifestyle changes and drug therapy to manage their IBS-C. Several categories of drugs have been used to treat IBS-C symptoms, including bulkforming, stimulant, and osmotic laxatives as well as stool softeners and lubricants. These drugs are not indicated or proven to be effective in the relief of global symptoms. Agents such as psyllium, methylcellulose, calcium polycarbophil, lactulose, sorbitol, polyethylene glycol, and magnesium hydroxide may be effective for constipation, but treatment of IBS-C should be aimed at relieving global symptoms. 1,2 Antispasmodics such as hyoscyamine and dicyclomine have been studied in patients with IBS-C, but there are insufficient data to recommend these agents for global symptom control. 1 Even probiotics have been tried in IBS-C patients to decrease abdominal pain and bloating, but none of these agents have been proven effective and safe for chronic use in treating the global symptoms of IBS-C. Zelnorm (tegaserod maleate), a 5-HT 4 (serotonin) receptor agonist used to decrease transit time and increase intestinal secretion in women with IBS-C, was until recently available only under a restricted-access program due to its potential for increasing the chance of heart attack, stroke, and worsening heart chest pain that could lead to a heart attack. 6 This restrictedaccess program was closed April 2, 2008, making this drug currently unavailable for general use, except for as an emergency investigational new drug (IND) application option available through the FDA. 7 FOCUS ON AMITIZA AMITIZA 8 mcg twice daily received approval by the FDA for the treatment of IBS-C in women 18 years old. PHARMACOLOGY Lubiprostone activates chloride channels (ClC-2) in the apical 3

4 Management of IBS-C in Women 18 Years of Age and Older (luminal) membrane of the gastrointestinal epithelium, thereby enhancing the secretion of a chloride-rich intestinal fluid without altering serum electrolyte levels. This activity results in increased motility in the intestine and facilitates the passage of stool. 8 PHARMACOKINETIC PROFILE Lubiprostone has low systemic availability following oral administration and plasma concentrations are below the level of quantitation (10 pg/ml). Studies in rats given radiolabeled lubiprostone indicate minimal distribution beyond the gastrointestinal tissues. In vitro studies using human liver microsomes indicate that microsomal carbonyl reductase may be involved in the extensive biotransformation of lubiprostone. Further in vitro studies indicate that cytochrome P450 isoenzymes are not involved in the metabolism of lubiprostone. The M3 metabolite, the only measurable active metabolite of lubiprostone, makes up less than 10% of the dose of radiolabeled lubiprostone. 8 Peak plasma levels of M3, after a single oral dose of 24 mcg of lubiprostone, occurred at approximately 1.10 hours. In vitro protein binding studies indicate lubiprostone is approximately 94% protein bound. 8 The effect of food on the pharmacokinetics of a 72 mcg dose of radiolabeled lubiprostone showed the C max decreased by 55% while the AUC 0-8 was unchanged when lubiprostone was administered with a high-fat meal. The clinical relevance of the effect of food on the pharmacokinetics of lubiprostone is not clear. However, lubiprostone was administered with food and water in a majority of clinical trials. Dosage and administration instructions for lubiprostone state that lubiprostone be taken twice daily orally with food and water. 8 EFFICACY IN CLINICAL TRIALS AMITIZA 8 mcg, 16 mcg, and 24 mcg, twice daily, were studied in a dose-finding, double-blinded, randomized, placebo-controlled Phase 2 study of 195 adult patients with IBS-C. The primary endpoint was a change from baseline in abdominal discomfort or pain during the first treatment month. 9 Given the favorable combination of efficacy and safety profiles seen with the 8 mcg twice daily dose, this dose was chosen for Phase 3 evaluation. AMITIZA 8 mcg twice daily was studied in 2 doubleblinded, placebo-controlled clinical trials of similar design in patients with IBS-C. IBS was defined as having abdominal pain or discomfort occurring over at least 6 months with 2 or more of the following: 1) relieved with defecation; 2) onset associated with a change in frequency of stool; and 3) onset associated with a change in form of stool. Patients were sub-typed as having IBS-C if they also experienced 2 of 3 of the following: 1) <3 spontaneous bowel movements per week; 2) >25% hard stools; and 3) >25% spontaneous bowel movements associated with straining. 8 In the 2 studies, an intent-to-treat population of 1154 patients were randomized and received AMITIZA 8 mcg twice daily or placebo twice daily for 12 weeks. The primary efficacy endpoint was assessed weekly using the patient s response to a global symptom relief question based on a 7-point, balanced scale. Patients considered to be overall responders (the primary endpoint of the study) were 13.8% (N=390) and 12.1% (N=379), compared to 7.8% (N=193) and 5.7% (N=192), respectively, in the placebo groups. In both studies, the treatment differences between the placebo and AMITIZA groups were statistically significant. Study 1 4

5 Management of IBS-C in Women 18 Years of Age and Older also assessed the rebound effect from the withdrawal of AMITIZA. Following the 12 weeks of treatment with AMITIZA 8 mcg twice daily, withdrawal of AMITIZA did not result in a rebound effect. 8 In general, AMITIZA 8 mcg twice daily was well tolerated in clinical trials and has a demonstrated safety and efficacy profile for adult female patients with IBS-C. The most common adverse reactions in 1011 patients through 1 year on AMITIZA 8 mcg twice daily (incidence greater than 1%) were nausea (8%), diarrhea (7%), abdominal pain (5%), and abdominal distension (3%) versus 435 patients up to 16 weeks on placebo (4%, 4%, 5%, and 2%, respectively). 8 CONTRAINDICATIONS, WARNINGS, AND PRECAUTIONS AMITIZA is contraindicated in patients with known or suspected mechanical gastrointestinal obstruction. In patients with symptoms suggestive of mechanical gastrointestinal obstruction, the treating healthcare provider should perform a thorough evaluation to confirm the absence of such an obstruction prior to initiating therapy with AMITIZA. 8 The safety of AMITIZA in pregnancy has not been evaluated in humans. AMITIZA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Women who could become pregnant should have a negative pregnancy test prior to beginning therapy with AMITIZA and should be capable of complying with effective contraceptive measures. 8 Patients taking AMITIZA may experience nausea. If this occurs, concomitant administration of food with AMITIZA may reduce symptoms of nausea. AMITIZA should not be prescribed to patients who have severe diarrhea. Patients should be aware of the possibility of diarrhea during treatment, and should be instructed to inform their physician if severe diarrhea and nausea occur. 8 In post-marketing clinical trials studying AMITIZA 8 mcg twice daily, there were reports of dyspnea at 0.4% in the treated IBS-C population. These events have usually been described as a sensation of chest tightness and difficulty taking in a breath, and generally have an acute onset within 30 to 60 minutes after taking the first dose. These symptoms generally resolve within a few hours after taking the dose, but recurrence has been frequently reported with subsequent doses. 8 DRUG INTERACTIONS Based upon the results of in vitro human microsome studies, there is low likelihood of drug-drug interactions with lubiprostone. In vitro studies using human liver microsomes indicate that cytochrome P450 isoenzymes are not involved in the metabolism of lubiprostone. No additional drug-drug interaction studies have been performed. Based on the available information, no protein binding-mediated drug interactions of clinical significance are anticipated. 8 CONCLUSION Although the underlying pathophysiology is not completely understood and there is no specific test or cure for IBS-C, patients can learn to manage their symptoms with diet, lifestyle changes, and drug therapy. Pharmacists have the opportunity to refer patients who suffer from the symptoms of IBS-C to their physicians, who now have a demonstrated, well-tolerated, and efficacious therapy available to treat this condition. AMITIZA 8 mcg gelcaps taken twice daily is an approved treatment for adult women who suffer from IBS-C. See Important Safety Information on next page. 5

6 Important Safety Information Indication AMITIZA (lubiprostone) is indicated for the treatment of Irritable Bowel Syndrome with Constipation (8 mcg twice daily) in women 18 years old. Important Safety Information AMITIZA is contraindicated in patients with known or suspected mechanical gastrointestinal obstruction. Patients with symptoms suggestive of mechanical gastrointestinal obstruction should be thoroughly evaluated by the treating healthcare provider to confirm the absence of such an obstruction prior to initiating AMITIZA treatment. The safety of AMITIZA in pregnancy has not been evaluated in humans. AMITIZA should be used during pregnancy only if the benefit justifies the potential risk to the fetus. Women who could become pregnant should have a negative pregnancy test prior to beginning therapy with AMITIZA and should be capable of complying with effective contraceptive measures. Patients taking AMITIZA may experience nausea. If this occurs, concomitant administration of food with AMITIZA may reduce symptoms of nausea. Patients who experience severe nausea should inform their healthcare provider. AMITIZA should not be prescribed to patients that have severe diarrhea. Patients should be aware of the possible occurrence of diarrhea during treatment and inform their healthcare provider if the diarrhea becomes severe. Patients taking AMITIZA may experience dyspnea within an hour of first dose. This symptom generally resolves within three hours, but may recur with repeat dosing. Patients who experience dyspnea should inform their healthcare provider. Some patients have discontinued therapy because of dyspnea. In clinical trials of AMITIZA (8 mcg twice daily vs placebo; N=1011 vs N=435) in patients with Irritable Bowel Syndrome with Constipation, the most common adverse reactions (incidence > 4%) were nausea (8% vs 4%), diarrhea (7% vs 4%), and abdominal pain (5% vs 5%). Please see the accompanying complete prescribing information for AMITIZA. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit or call FDA

7 Management of IBS-C in Women 18 Years of Age and Older REFERENCES 1. American College of Gastroenterology Functional Gastrointestinal Disorders Task Force. Evidence-based position statement on the management of irritable bowel syndrome in North America. Gastroenterology Nov;97(11suppl):S1-S5. 2. Longstreth GF, Thompson WG, Chey WD, et al. Functional bowel disorders. Gastroenterology Apr;130(5): Hungin AP, Chang L, Locke GR, et al. Irritable bowel syndrome in the United States: prevalence, symptom patterns and impact. Aliment Pharmacol Ther Jun1;21(11): Malagelada JR. A symptom-based approach to making a positive diagnosis of irritable bowel syndrome with constipation. Int J Clin Pract Jan;60(1): American Gastroenterological Association. American Gastroenterological Association medical position statement: irritable bowel syndrome. Gastroenterology Dec;123(6): FDA Public Health Advisory. Tegaserod maleate (marketed as Zelnorm). Available at fda.gov/cder/drug/advisory/tegaserod. htm. Accessed April 15, Novartis Pharmaceuticals. Zelnorm (tegaserod maleate). Available at com/index.jsp. Accessed April 15, AMITIZA [package insert]. Bethesda, MD: Sucampo Pharmaceuticals, Inc.; Data on file. Resources on Irritable Bowel Syndrome with Constipation National Digestive Diseases Information Clearinghouse 2 Information Way Bethesda, MD Phone: American Gastroenterological Association 4930 Del Ray Avenue Bethesda, MD Phone: American College of Gastroenterology P.O. Box Bethesda, MD Phone: International Foundation for Functional Gastrointestinal Disorders (IFFGD), Inc. P.O. Box Milwaukee, WI Phone: or 7

8 Notes 8

9 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Amitiza safely and effectively. See full prescribing information for Amitiza. Amitiza (lubiprostone) Capsules Initial U.S. Approval: RECENT MAJOR CHANGES Indications and Usage (1.2) 4/2008 Dosage and Administration (2.2) 4/2008 Warnings and Precautions (5.4) 4/ INDICATIONS AND USAGE Amitiza is a chloride channel activator indicated for: Treatment of chronic idiopathic constipation in adults (1.1) Treatment of irritable bowel syndrome with constipation in women 18 years old (1.2) DOSAGE AND ADMINISTRATION to initiating treatment with Amitiza (5.5) Chronic idiopathic constipation 24 mcg taken twice daily orally with food and water (2.1) Irritable bowel syndrome with constipation 8 mcg taken twice daily orally with food and water (2.2) DOSAGE FORMS AND STRENGTHS Gelatin capsules: 8 mcg and 24 mcg (3) CONTRAINDICATIONS Patients with known or suspected mechanical gastrointestinal obstruction should not receive Amitiza (4) WARNINGS AND PRECAUTIONS Women who could become pregnant should FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Chronic Idiopathic Constipation 1.2 Irritable Bowel Syndrome with Constipation 2 DOSAGE AND ADMINISTRATION 2.1 Chronic Idiopathic Constipation 2.2 Irritable Bowel Syndrome with Constipation 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Pregnancy 5.2 Nausea 5.3 Diarrhea 5.4 Dyspnea 5.5 Bowel Obstruction 6 ADVERSE REACTIONS 6.1 Clinical Studies Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use have a negative pregnancy test prior to beginning therapy and should be capable of complying with effective contraceptive measures (8.1) Use during pregnancy only if the potential benefit justifies the potential risk to the fetus (5.1) Patients may experience nausea; concomitant administration of food may reduce this symptom (5.2) Do not prescribe for patients that have severe diarrhea (5.3) Patients taking Amitiza may experience dyspnea within an hour of first dose. This symptom generally resolves within 3 hours, but may recur with repeat dosing (5.4) Evaluate patients with symptoms suggestive of mechanical gastrointestinal obstruction prior ADVERSE REACTIONS Most common adverse reactions (incidence > 4%) in chronic idiopathic constipation are nausea, diarrhea, headache, abdominal pain, abdominal distension, and flatulence (6.1) Most common adverse reactions (incidence > 4%) in irritable bowel syndrome with constipation are nausea, diarrhea, and abdominal pain (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals at or FDA at FDA-1088 or See 17 for PATIENT COUNSELING INFORMATION Revised: Apr/ Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Chronic Idiopathic Constipation 14.2 Irritable Bowel Syndrome with Constipation 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION 17.1 Dosing Instructions *Sections or subsections omitted from the full prescribing information are not listed FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 1.1 Chronic Idiopathic Constipation Amitiza is indicated for the treatment of chronic idiopathic constipation in adults. 1.2 Irritable Bowel Syndrome with Constipation Amitiza is indicated for the treatment of irritable bowel syndrome with constipation (IBS-C) in women 18 years old. 2 DOSAGE AND ADMINISTRATION Amitiza should be taken twice daily orally with food and water. Physicians and patients should periodically assess the need for continued therapy. 2.1 Chronic Idiopathic Constipation 24 mcg twice daily orally with food and water. 2.2 Irritable Bowel Syndrome with Constipation 8 mcg twice daily orally with food and water. 3 DOSAGE FORMS AND STRENGTHS Amitiza is available as an oval, gelatin capsule containing 8 mcg or 24 mcg of lubiprostone. 8-mcg capsules are pink and are printed with SPI on one side 24-mcg capsules are orange and are printed with SPI on one side 4 CONTRAINDICATIONS Amitiza is contraindicated in patients with known or suspected mechanical gastrointestinal obstruction. 5 WARNINGS AND PRECAUTIONS 5.1 Pregnancy The safety of Amitiza in pregnancy has not been evaluated in humans. In guinea pigs, lubiprostone has been shown to have the potential to cause fetal loss. Amitiza should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Women who could become pregnant should have a negative pregnancy test prior to beginning therapy with Amitiza and should be capable of complying with effective contraceptive measures. See Use in Specific Populations (8.1). 5.2 Nausea Patients taking Amitiza may experience nausea. If this occurs, concomitant administration of food with Amitiza may reduce symptoms of nausea. See Adverse Reactions (6.1). 5.3 Diarrhea Amitiza should not be prescribed to patients that have severe diarrhea. Patients should be aware of the possible occurrence of diarrhea during treatment. Patients should be instructed to inform their physician if severe diarrhea occurs. See Adverse Reactions (6.1). 5.4 Dyspnea In clinical trials conducted to study Amitiza in treatment of chronic idiopathic constipation and IBS-C there were reports of dyspnea. This was reported at 2.5% of the treated chronic idiopathic constipation population and at 0.4% in the treated IBS-C population. Although not classified as serious adverse events, some patients discontinued treatment on study because of this event. There have been postmarketing reports of dyspnea when using Amitiza 24 mcg. Most have not been characterized as serious adverse events, but some patients have discontinued therapy because of dyspnea. These events have usually been described as a sensation of chest tightness and difficulty taking in a breath, and generally have an acute onset within minutes after taking the first dose. They generally resolve within a few hours after taking the dose, but recurrence has been frequently reported with subsequent doses. 5.5 Bowel Obstruction In patients with symptoms suggestive of mechanical gastrointestinal obstruction, the treating physician should perform a thorough evaluation to confirm the absence of such an obstruction prior to initiating therapy with Amitiza. 6 ADVERSE REACTIONS 6.1 Clinical Studies Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Chronic Idiopathic Constipation Adverse reactions in dose-finding, efficacy, and long-term clinical studies: The data described below reflect exposure to Amitiza in 1175 patients with chronic idiopathic constipation (29 at 24 mcg once daily, 1113 at 24 mcg twice daily, and 33 at 24 mcg three times daily) over 3- or 4-week, 6-month, and 12-month treatment periods; and from 316 patients receiving placebo over short-term exposure ( 4 weeks). The total population (N = 1491) had a mean age of 49.7 (range 19 86) years; was 87.1% female; 84.8% Caucasian, 8.5% African American, 5.0% Hispanic, 0.9% Asian; and 15.5% elderly ( 65 years of age). Table 1 presents data for the adverse reactions that occurred in at least 1% of patients who received Amitiza 24 mcg twice daily and that occurred more frequently with study drug than placebo. In addition, corresponding adverse reaction incidence rates in patients receiving Amitiza 24 mcg once daily is shown. Table 1: Percent of Patients with Adverse Reactions (Chronic Idiopathic Constipation) Placebo Amitiza Amitiza 24 mcg 24 mcg System/Adverse Reaction 1 Once Daily Twice Daily N = 316 N = 29 N = 1113 % % % Gastrointestinal disorders Nausea Diarrhea < Abdominal pain Abdominal distension 2-6 Flatulence Vomiting Loose stools Abdominal discomfort 2 < Dyspepsia < 1-2 Dry mouth < 1-1 Stomach discomfort < 1-1 Nervous system disorders Headache Dizziness < General disorders and site administration conditions Edema < 1-3 Fatigue < 1-2 Chest discomfort/pain Respiratory, thoracic, and mediastinal disorders Dyspnea Includes only those events associated with treatment (possibly, probably, or definitely related, as assessed by the investigator). 2 This term combines abdominal tenderness, abdominal rigidity, gastrointestinal discomfort, and abdominal discomfort. Nausea: Approximately 29% of patients who received Amitiza 24 mcg twice daily experienced an adverse reaction of nausea; 4% of patients had severe nausea while 9% of patients discontinued treatment due to nausea. The rate of nausea associated with Amitiza (any dosage) was substantially lower among male (7%) and elderly patients (18%). Further analysis of the safety data revealed that long-term exposure to Amitiza does not appear to place patients at an elevated risk for experiencing nausea. The incidence of nausea increased in a dose-dependent manner with the lowest overall incidence for nausea reported at the 24 mcg once daily dosage (17%). In open-labeled, long-term studies, patients were allowed to adjust the dosage of Amitiza down to 24 mcg once daily from 24 mcg twice daily if experiencing nausea. Nausea decreased when Amitiza was administered with food. No patients in the clinical studies were hospitalized due to nausea. Diarrhea: Approximately 12% of patients who received Amitiza 24 mcg twice daily experienced an adverse reaction of diarrhea; 2% of patients had severe diarrhea while 2% of patients discontinued treatment due to diarrhea. Electrolytes: No serious adverse reactions of electrolyte imbalance were reported in clinical studies, and no clinically significant changes were seen in serum electrolyte levels in patients receiving Amitiza. Less common adverse reactions: The following adverse reactions (assessed by investigator as probably or definitely related to treatment) occurred in less than 1% of patients receiving Amitiza 24 mcg twice daily in clinical studies, occurred in at least two patients, and occurred more frequently in patients receiving study drug than those receiving placebo: fecal incontinence, muscle cramp, defecation urgency, frequent bowel movements, hyperhidrosis, pharyngolaryngeal pain, intestinal

10 functional disorder, anxiety, cold sweat, constipation, cough, dysgeusia, eructation, influenza, joint swelling, myalgia, pain, syncope, tremor, decreased appetite. Irritable Bowel Syndrome with Constipation Adverse reactions in dose-finding, efficacy, and long-term clinical studies: The data described below reflect exposure to Amitiza 8 mcg twice daily in 1011 patients with IBS-C for up to 12 months and from 435 patients receiving placebo twice daily for up to 16 weeks. The total population (N = 1267) had a mean age of 46.5 (range 18 85) years; was 91.6% female; 77.5% Caucasian, 12.9% African American, 8.6% Hispanic, 0.4% Asian; and 8.0% elderly ( 65 years of age). Table 2 presents data for the adverse reactions that occurred in at least 1% of patients who received Amitiza 8 mcg twice daily and that occurred more frequently with study drug than placebo. Table 2: Percent of Patients with Adverse Reactions (IBS-C Studies) Placebo Amitiza System/Adverse Reaction 1 8 mcg Twice Daily N = 435 N = 1011 % % Gastrointestinal disorders Nausea 4 8 Diarrhea 4 7 Abdominal pain 5 5 Abdominal distension Includes only those events associated with treatment (possibly or probably related, as assessed by the investigator). Less common adverse reactions: The following adverse reactions (assessed by investigator as probably related to treatment) occurred in less than 1% of patients receiving Amitiza 8 mcg twice daily in clinical studies, occurred in at least two patients, and occurred more frequently in patients receiving study drug than those receiving placebo: dyspepsia, loose stools, vomiting, fatigue, dry mouth, edema, increased alanine aminotransferase, increased aspartate aminotransferase, constipation, eructation, gastroesophageal reflux disease, dyspnea, erythema, gastritis, increased weight, palpitations, urinary tract infection, anorexia, anxiety, depression, fecal incontinence, fibromyalgia, hard feces, lethargy, rectal hemorrhage, pollakiuria. One open-labeled, long-term clinical study was conducted in patients with IBS-C receiving Amitiza 8 mcg twice daily. This study comprised 476 intent-to-treat patients (mean age 47.5 [range 21 82] years; 93.5% female; 79.2% Caucasian, 11.6% African American, 8.6% Hispanic, 0.2% Asian; 7.8% 65 years of age) who were treated for an additional 36 weeks following an initial week, double-blinded treatment period. The adverse reactions that were reported during this study were similar to those observed in the two double-blinded, controlled studies. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of Amitiza 24 mcg for the treatment of chronic idiopathic constipation. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Voluntary reports of adverse reactions occurring with the use of Amitiza include the following: syncope, allergic-type reactions (including rash, swelling, and throat tightness), malaise, increased heart rate, muscle cramps or muscle spasms, rash, and asthenia. 7 DRUG INTERACTIONS Based upon the results of in vitro human microsome studies, there is low likelihood of drug drug interactions. In vitro studies using human liver microsomes indicate that cytochrome P450 isoenzymes are not involved in the metabolism of lubiprostone. Further in vitro studies indicate microsomal carbonyl reductase may be involved in the extensive biotransformation of lubiprostone to the metabolite M3 (See Pharmacokinetics [12.3].). Additionally, in vitro studies in human liver microsomes demonstrate that lubiprostone does not inhibit cytochrome P450 isoforms 3A4, 2D6, 1A2, 2A6, 2B6, 2C9, 2C19, or 2E1, and in vitro studies of primary cultures of human hepatocytes show no induction of cytochrome P450 isoforms 1A2, 2B6, 2C9, and 3A4 by lubiprostone. No additional drug drug interaction studies have been performed. Based on the available information, no protein binding mediated drug interactions of clinical significance are anticipated. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic effects: Pregnancy Category C. [See Warnings and Precautions (5.1).] Teratology studies with lubiprostone have been conducted in rats at oral doses up to 2000 mcg/kg/day (approximately 332 times the recommended human dose, based on body surface area), and in rabbits at oral doses of up to 100 mcg/kg/day (approximately 33 times the recommended human dose, based on body surface area). Lubiprostone was not teratogenic in rats or rabbits. In guinea pigs, lubiprostone caused fetal loss at repeated doses of 10 and 25 mcg/kg/day (approximately 2 and 6 times the highest recommended human dose, respectively, based on body surface area) administered on days 40 to 53 of gestation. There are no adequate and well-controlled studies in pregnant women. However, during clinical testing of Amitiza, six women became pregnant. Per protocol, Amitiza was discontinued upon pregnancy detection. Four of the six women delivered healthy babies. The fifth woman was monitored for 1 month following discontinuation of study drug, at which time the pregnancy was progressing as expected; the patient was subsequently lost to follow-up. The sixth pregnancy was electively terminated. Amitiza should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. If a woman is or becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to the fetus. 8.3 Nursing Mothers It is not known whether lubiprostone is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from lubiprostone, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been studied. 8.5 Geriatric Use Chronic Idiopathic Constipation The efficacy of Amitiza in the elderly ( 65 years of age) subpopulation was consistent with the efficacy in the overall study population. Of the total number of constipated patients treated in the dose-finding, efficacy, and long-term studies of Amitiza, 15.5% were 65 years of age, and 4.2% were 75 years of age. Elderly patients taking Amitiza (any dosage) experienced a lower incidence rate of associated nausea compared to the overall study population taking Amitiza (18% vs. 29%, respectively). Irritable Bowel Syndrome with Constipation The safety profile of Amitiza in the elderly ( 65 years of age) subpopulation (8.0% were 65 years of age and 1.8% were 75 years of age) was consistent with the safety profile in the overall study population. Clinical studies of Amitiza did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients. 8.6 Renal Impairment Amitiza has not been studied in patients who have renal impairment. 8.7 Hepatic Impairment Amitiza has not been studied in patients who have hepatic impairment. 10 OVERDOSAGE There have been two confirmed reports of overdosage with Amitiza. The first report involved a 3-year-old child who accidentally ingested 7 or 8 capsules of 24 mcg of Amitiza and fully recovered. The second report was a study patient who self-administered a total of 96 mcg of Amitiza per day for 8 days. The patient experienced no adverse reactions during this time. Additionally, in a Phase 1 cardiac repolarization study, 38 of 51 patients given a single oral dose of 144 mcg of Amitiza (6 times the highest recommended dose) experienced an adverse event that was at least possibly related to the study drug. Adverse reactions that occurred in at least 1% of these patients included the following: nausea (45%), diarrhea (35%), vomiting (27%), dizziness (14%), headache (12%), abdominal pain (8%), flushing/hot flash (8%), retching (8%), dyspnea (4%), pallor (4%), stomach discomfort (4%), anorexia (2%), asthenia (2%), chest discomfort (2%), dry mouth (2%), hyperhidrosis (2%), and syncope (2%). 11 DESCRIPTION Amitiza (lubiprostone) is chemically designated as ( )-7-[(2R,4aR,5R,7aR)-2-(1,1-difluoropentyl)- 2-hydroxy-6-oxooctahydrocyclopenta[b]pyran-5-yl]heptanoic acid. The molecular formula of lubiprostone is C 20 H 32 F 2 O 5 with a molecular weight of and a chemical structure as follows: O O H H O H HO F F CH 3 Lubiprostone drug substance occurs as white, odorless crystals or crystalline powder, is very soluble in ether and ethanol, and is practically insoluble in hexane and water. Amitiza is available as an imprinted, oval, soft gelatin capsule in two strengths. Pink capsules contain 8 mcg of lubiprostone and the following inactive ingredients: medium-chain triglycerides, gelatin, sorbitol, ferric oxide, titanium dioxide, and purified water. Orange capsules contain 24 mcg of lubiprostone and the following inactive ingredients: medium-chain triglycerides, gelatin, sorbitol, FD&C Red #40, D&C Yellow #10, and purified water. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Lubiprostone is a locally acting chloride channel activator that enhances a chloride-rich intestinal fluid secretion without altering sodium and potassium concentrations in the serum. Lubiprostone acts by specifically activating ClC-2, which is a normal constituent of the apical membrane of the human intestine, in a protein kinase A independent fashion. By increasing intestinal fluid secretion, lubiprostone increases motility in the intestine, thereby facilitating the passage of stool and alleviating symptoms associated with chronic idiopathic constipation. Patch clamp cell studies in human cell lines have indicated that the majority of the beneficial biological activity of lubiprostone and its metabolites is observed only on the apical (luminal) portion of the gastrointestinal epithelium. Additionally, activation of ClC-2 by lubiprostone has been shown to stimulate recovery of mucosal barrier function via the restoration of tight junction protein complexes in ex vivo studies of ischemic porcine intestine Pharmacodynamics Although the pharmacologic effects of lubiprostone in humans have not been fully evaluated, animal studies have shown that oral administration of lubiprostone increases chloride ion transport into the intestinal lumen, enhances fluid secretion into the bowels, and improves fecal transit Pharmacokinetics Lubiprostone has low systemic availability following oral administration and concentrations of lubiprostone in plasma are below the level of quantitation (10 pg/ml). Therefore, standard pharmacokinetic parameters such as area under the curve (AUC), maximum concentration (C max ), and half-life (t1/2) cannot be reliably calculated. However, the pharmacokinetic parameters of M3 (only measurable active metabolite of lubiprostone) have been characterized. Gender has no effect on the pharmacokinetics of M3 following the oral administration of lubiprostone. Absorption Concentrations of lubiprostone in plasma are below the level of quantitation (10 pg/ml) because lubiprostone has a low systemic availability following oral administration. Peak plasma levels of M3, after a single oral dose with 24 mcg of lubiprostone, occurred at approximately 1.10 hours. The C max was 41.5 pg/ml and the mean AUC 0 t was 57.1 pg hr/ml. The AUC 0 t of M3 increases dose proportionally after single 24-mcg and 144-mcg doses of lubiprostone. Distribution In vitro protein binding studies indicate lubiprostone is approximately 94% bound to human plasma proteins. Studies in rats given radiolabeled lubiprostone indicate minimal distribution beyond the gastrointestinal tissues. Concentrations of radiolabeled lubiprostone at 48 hours post-administration were minimal in all tissues of the rats. Metabolism The results of both human and animal studies indicate that lubiprostone is rapidly and extensively metabolized by 15-position reduction, α-chain β-oxidation, and ω-chain ω-oxidation. These biotransformations are not mediated by the hepatic cytochrome P450 system but rather appear to be mediated by the ubiquitously expressed carbonyl reductase. M3, a metabolite of lubiprostone found in both humans and animals, is formed by the reduction of the carbonyl group at the 15-hydroxy moiety that consists of both α-hydroxy and β-hydroxy epimers. M3 makes up less than 10% of the dose of radiolabeled lubiprostone. Animal studies have shown that metabolism of lubiprostone rapidly occurs within the stomach and jejunum, most likely in the absence of any systemic absorption. This is presumed to be the case in humans as well. Elimination Lubiprostone could not be detected in plasma; however, M3 has a t1/2 ranging from 0.9 to 1.4 hours. After a single oral dose of 72 mcg of 3 H-labeled lubiprostone, 60% of total administered radioactivity was recovered in the urine within 24 hours and 30% of total administered radioactivity was recovered in the feces by 168 hours. Lubiprostone and M3 are only detected in trace amounts in human feces. Food Effect A study was conducted with a single 72-mcg dose of 3 H-labeled lubiprostone to evaluate the potential of a food effect on lubiprostone absorption, metabolism, and excretion. Pharmacokinetic parameters of total radioactivity demonstrated that C max decreased by 55% while AUC 0 was unchanged when lubiprostone was administered with a high-fat meal. The clinical relevance of the effect of food on the pharmacokinetics of lubiprostone is not clear. However, lubiprostone was administered with food and water in a majority of clinical trials. OH

11 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Two 2-year oral (gavage) carcinogenicity studies (one in Crl:B6C3F1 mice and one in Sprague-Dawley rats) were conducted with lubiprostone. In the 2-year carcinogenicity study in mice, lubiprostone doses of 25, 75, 200, and 500 mcg/kg/day (approximately 2, 6, 17, and 42 times the highest recommended human dose, respectively, based on body surface area) were used. In the 2-year rat carcinogenicity study, lubiprostone doses of 20, 100, and 400 mcg/kg/day (approximately 3, 17, and 68 times the highest recommended human dose, respectively, based on body surface area) were used. In the mouse carcinogenicity study, there was no significant increase in any tumor incidences. There was a significant increase in the incidence of interstitial cell adenoma of the testes in male rats at the 400 mcg/kg/day dose. In female rats, treatment with lubiprostone produced hepatocellular adenoma at the 400 mcg/kg/day dose. Mutagenesis Lubiprostone was not genotoxic in the in vitro Ames reverse mutation assay, the in vitro mouse lymphoma (L5178Y TK +/- ) forward mutation assay, the in vitro Chinese hamster lung (CHL/IU) chromosomal aberration assay, and the in vivo mouse bone marrow micronucleus assay. Impairment of Fertility Lubiprostone, at oral doses of up to 1000 mcg/kg/day, had no effect on the fertility and reproductive function of male and female rats. However, the number of implantation sites and live embryos were significantly reduced in rats at the 1000 mcg/kg/day dose as compared to control. The number of dead or resorbed embryos in the 1000 mcg/kg/day group was higher compared to the control group, but was not statistically significant. The 1000 mcg/kg/day dose in rats is approximately 166 times the highest recommended human dose of 48 mcg/day, based on body surface area. 14 CLINICAL STUDIES 14.1 Chronic Idiopathic Constipation Dose-finding Study A dose-finding, double-blinded, parallel-group, placebo-controlled, Phase 2 study was conducted in patients with chronic idiopathic constipation. Following a 2-week baseline/washout period, patients (N = 127) were randomized to receive placebo (n = 33), Amitiza 24 mcg/day (24 mcg once daily; n = 29), Amitiza 48 mcg/day (24 mcg twice daily; n = 32), or Amitiza 72 mcg/day (24 mcg three times daily; n = 33) for 3 weeks. Patients were chosen for participation based on their need for relief of constipation, which was defined as less than 3 spontaneous bowel movements (SBMs) per week. The primary efficacy variable was the daily average number of SBMs. The study demonstrated that all patients who took Amitiza experienced a noticeable improvement in clinical response. Based on the efficacy analysis, there was no statistically significant improvement in the clinical response beyond a total daily dose of 24 mcg during treatment weeks 2 and 3 (Figure 1). Placebo 24 mcg QD 24 mcg BID 24 mcg TID Baseline Week 1 Week 2 Week 3 Figure 1: Weekly Mean (± Standard Error) Spontaneous Bowel Movements (Dose-finding Study) Efficacy Studies Two double-blinded, placebo-controlled studies of identical design were conducted in patients with chronic idiopathic constipation. Chronic idiopathic constipation was defined as, on average, less than 3 SBMs per week along with one or more of the following symptoms of constipation for at least 6 months prior to randomization: 1) very hard stools for at least a quarter of all bowel movements; 2) sensation of incomplete evacuation following at least a quarter of all bowel movements; and 3) straining with defecation at least a quarter of the time. Following a 2-week baseline/washout period, a total of 479 patients (mean age 47.2 [range 20 81] years; 88.9% female; 80.8% Caucasian, 9.6% African American, 7.3% Hispanic, 1.5% Asian; 10.9% 65 years of age) were randomized and received Amitiza 24 mcg twice daily (48 mcg/day) or placebo twice daily for 4 weeks. The primary endpoint of the studies was SBM frequency. The studies demonstrated that patients treated with Amitiza had a higher frequency of SBMs during Week 1 than the placebo patients. In both studies, results similar to those in Week 1 were also observed in Weeks 2, 3, and 4 of therapy (Table 3). Table 3: Spontaneous Bowel Movement Frequency Rates 1 (Efficacy Studies) Week 1 Week 4 Baseline Week 1 Week 2 Week 3 Week 4 Change from Change from Study Weekly Mean SBMs Trial Mean ± SD Mean ± SD Mean ± SD Mean ± SD Mean ± SD Baseline Baseline Arm Median Median Median Median Median Mean ± SD Mean ± SD Median Median 1.6 ± ± ± ± ± ± ± 2.5 Placebo Study 1 Amitiza 24 mcg 1.4 ± ± ± ± ± ± ± 4.6 Twice Daily ± ± ± ± ± ± ± 2.7 Placebo Study 2 Amitiza 24 mcg 1.3 ± ± ± ± ± ± ± 4.8 Twice Daily Frequency rates are calculated as 7 times (number of SBMs) / (number of days observed for that week). In both studies, Amitiza demonstrated increases in the percentage of patients who experienced SBMs within the first 24 hours after administration when compared to placebo (56.7% vs. 36.9% in Study 1 and 62.9% vs. 31.9% in Study 2, respectively). Similarly, the time to first SBM was shorter for patients receiving Amitiza than for those receiving placebo. Signs and symptoms related to constipation, including abdominal bloating, abdominal discomfort, stool consistency, and straining, as well as constipation severity ratings, were also improved with Amitiza versus placebo. The results were consistent in subpopulation analyses for gender, race, and elderly patients ( 65 years of age). Following 4 weeks of treatment with Amitiza 24 mcg twice daily, withdrawal of Amitiza did not result in a rebound effect. Long-term Studies Three open-labeled, long-term clinical safety and efficacy studies were conducted in patients with chronic idiopathic constipation receiving Amitiza 24 mcg twice daily. These studies comprised 871 patients (mean age 51.0 [range 19 86] years; 86.1% female; 86.9% Caucasian, 7.3% African American, 4.5% Hispanic, 0.7% Asian; 18.4% 65 years of age) who were treated for 6 12 months (24 48 weeks). Patients provided regular assessments of abdominal bloating, abdominal discomfort, and constipation severity. These studies demonstrated that Amitiza decreased abdominal bloating, abdominal discomfort, and constipation severity over the 6 12-month treatment periods Irritable Bowel Syndrome with Constipation Efficacy Studies Two double-blinded, placebo-controlled studies of similar design were conducted in patients with IBS-C. IBS was defined as abdominal pain or discomfort occurring over at least 6 months with two or more of the following: 1) relieved with defecation; 2) onset associated with a change in stool frequency; and 3) onset associated with a change in stool form. Patients were sub-typed as having IBS-C if they also experienced two of three of the following: 1) < 3 spontaneous bowel movements per week, 2) > 25% hard stools, and 3) > 25% spontaneous bowel movements associated with straining. Following a 4-week baseline/washout period, a total of 1154 patients (mean age 46.6 [range 18 85] years; 91.6% female; 77.4% Caucasian, 13.2% African American, 8.5% Hispanic, 0.4% Asian; 8.3% 65 years of age) were randomized and received Amitiza 8 mcg twice daily (16 mcg/day) or placebo twice daily for 12 weeks. The primary efficacy endpoint was assessed weekly utilizing the patient s response to a global symptom relief question based on a 7-point, balanced scale ( significantly worse to significantly relieved ): How would you rate your relief of IBS symptoms (abdominal discomfort/pain, bowel habits, and other IBS symptoms) over the past week compared to how you felt before you entered the study? The primary efficacy analysis was a comparison of the proportion of overall responders in each arm. A patient was considered an overall responder if the criteria for being designated a monthly responder were met in at least 2 of the 3 months on study. A monthly responder was defined as a patient who had reported significantly relieved for at least 2 weeks of the month or at least moderately relieved in all 4 weeks of that month. During each monthly evaluation period, patients reporting moderately worse or significantly worse relief, an increase in rescue medication use, or those who discontinued due to lack of efficacy, were deemed non-responders. The percentage of patients in Study 1 qualifying as an overall responder was 13.8% in the group receiving Amitiza 8 mcg twice daily compared to 7.8% of patients receiving placebo twice daily. In Study 2, 12.1% of patients in the Amitiza 8 mcg group were overall responders versus 5.7% of patients in the placebo group. In both studies, the treatment differences between the placebo and Amitiza groups were statistically significant. Results in men: The two randomized, placebo-controlled, double-blinded studies comprised 97 (8.4%) male patients, which is insufficient to determine whether men with IBS-C respond differently to Amitiza from women. Study 1 also assessed the rebound effect from the withdrawal of Amitiza. Following 12 weeks of treatment with Amitiza 8 mcg twice daily, withdrawal of Amitiza did not result in a rebound effect. 16 HOW SUPPLIED/STORAGE AND HANDLING Amitiza is available as an oval, soft gelatin capsule containing 8 mcg or 24 mcg of lubiprostone with SPI printed on one side. Amitiza is available as follows: 8-mcg pink capsule Bottles of 60 (NDC ) 24-mcg orange capsule Bottles of 60 (NDC ) Bottles of 100 (NDC ) Store at 25 C (77 F); excursions permitted to C (59 86 F). PROTECT FROM EXTREME TEMPERATURES. 17 PATIENT COUNSELING INFORMATION 17.1 Dosing Instructions Amitiza should be taken twice daily with food and water to reduce potential symptoms of nausea. The capsule should be taken once in the morning and once in the evening daily as prescribed. The capsule should be swallowed whole and should not be broken apart or chewed. Physicians and patients should periodically assess the need for continued therapy. Patients on treatment who experience severe nausea, diarrhea, or dyspnea should inform their physician. Patients taking Amitiza may experience dyspnea within an hour of the first dose. This symptom generally resolves within 3 hours, but may recur with repeat dosing. Chronic Idiopathic Constipation Patients should take a single 24 mcg capsule of Amitiza twice daily with food and water. Irritable Bowel Syndrome with Constipation Patients should take a single 8 mcg capsule of Amitiza twice daily with food and water. Marketed by: Amitiza is a registered trademark of Sucampo Pharmaceuticals, Inc Sucampo Pharmaceuticals, Inc /08 L-LUB Sucampo Pharmaceuticals, Inc. Bethesda, MD and Takeda Pharmaceuticals America, Inc. Deerfield, IL 60015